This invention relates to the treatment of impotence comprising co-administering (1) a potassium channel opener and (2) a compound which elevates cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) levels. The combination is particularly suitable for the treatment of patients suffering from impotence or erectile dysfunction.
Impotence is the inability to obtain and/or sustain an erection sufficient for penetration of the vagina and/or intercourse. Thus, impotence is also referred to as xe2x80x9cerectile insufficiencyxe2x80x9d or xe2x80x9cerectile dysfunctionxe2x80x9d. It has been estimated that 10-12 million American men between the ages of 18 and 75 suffer from chronic impotence, with the great majority being over age 55.
The penis normally becomes erect when certain tissues, in particular the corpora cavernosa in the central portion of the penis, become engorged with blood, thereby causing them to become less flaccid, and in turn causing an erection. Impotence can result from psychologic disturbances (psychogenic), from physiologic abnormalities (organic) or from a combination of both. Thus, in some males erectile dysfunction may be due to anxiety or depression, with no apparent somatic or organic impairment. In other cases, erectile dysfunction is associated with atherosclerosis of the arteries supplying blood to the penis. In still other cases, the dysfunction may be due to venous leakage or abnormal drainage in which there is leakage from veins in the penis such that sufficient pressure for an erection can be neither obtained nor maintained. In still other cases, the dysfunction is associated with a neuropathy or due to nerve damage arising from, for example, surgery or a pelvic injury. Typically, multiple factors are responsible for impotence.
Pharmacological, biophysical and molecular studies have revealed multiple subtypes for membrane ion channels that form potassium selective pores in the plasma membrane of many mammalian cells. One can classify the family of K channels simply by their respective gating properties. In other words, a comparison of the pharmacological and electrophysiological properties of potassium channels has given rise to an operational definition for grouping the various subtypes based largely on their gating properties. At present, potassium channels of known amino acid sequence comprise two distantly related protein families. One of these channel families is termed, xe2x80x9cvoltage-gated,xe2x80x9d the other channel family is termed xe2x80x9cinward rectifying.xe2x80x9d
The structure of the voltage-gated channel protein is known to be comprised of six membrane spanning domains in each subunit, each of which is regulated by changes in membrane potential. B. Hille, xe2x80x9cIonic Channels of Excitable Membranesxe2x80x9d (Sinauer, Sunderland, Mass., 1992). Voltage-gated potassium channels sense changes in membrane potential and move potassium ions in response to this alteration in the cell membrane potential. Molecular cloning studies on potassium channel proteins has yielded information primarily for members of the voltage-gated family of potassium channels. Various genes encoding these voltage-gated family of potassium channel proteins have been cloned using Drosophila genes derived from both the Shaker, Shaw and Shab loci; Wei, A. et. al., Science (1990) Vol. 248 pp. 599-603.
Unlike the voltage-gated channel proteins with six membrane spanning regions,the inward rectifier channels have only two membrane spanning domains, each sensitive to changes in the net potassium concentration. Within this class of channels are the ATP-sensitive potassium channels. These channels are classified by their sensitivity to concentration fluxes in ATP. The ATP-sensitive, or ATP-gated, potassium channel is an important class of channels that links the bioenergetic situation of the cell to changes in cell function. These channels are blocked by high intracellular ATP concentrations and are open when ATP decreases. Lazdunski (1992); M. Lazdunski et al., xe2x80x9cATP-Sensitive K less than + greater than  Channelsxe2x80x9d, Renal Physiol. Biochem. Vol. 17: pp. 118-120 (1994).
Although ATP-gated potassium channels were originally described in cardiac tissue, Noma, A. Nature (1983) Vol. 305 pp. 147-148, they have subsequently been described in pancreatic beta-cells, Cook et. al., Nature (1984) Vol. 311 pp. 271-273, vascular smooth muscle, Nelson, M. T. et. al., Am. J. Physiol. (1990) Vol. 259 pp. C3-C18 and in the thick ascending limb of the kidney, Wang, W. et. al. Am. J. Physiol. (1990) Vol. 258, pp. F244-F-253.
The ATP-sensitive or ATP-gated potassium channels play an important role in human physiology. The ATP-sensitive potassium channel, like other potassium channels, selectively regulate the cell""s permeability to potassium ions. These channels function to regulate the contraction and relaxation of the smooth muscle by opening or closing the channels in response to the modulation of receptors or potentials on the cell membrane. When ATP-sensitive potassium channels are opened, the increased permeability of the cell membrane allows more potassium ions to migrate outwardly so that the membrane potential shifts toward more negative values. When the membrane potential shifts toward more negative values the opening of the voltage-dependent calcium channels is reduced, this reduces the influx of calcium ions into the cell because the calcium channels become xe2x80x9cincreasingly less openxe2x80x9d as the membrane potential becomes more negative. Consequently, drugs having ATP-sensitive potassium channel opening activity, drugs known as potassium channel openers, can relax vascular smooth muscle and are useful as hypotensive and coronary vasodilating agents.
A relatively large number of compounds are now known which open cell membrane ATP-sensitive potassium channels, particularly in smooth muscle: minoxidil sulfate, diazoxide and nicorandil are well known potassium channel openers. The target site for these agents is presumably on the potassium channel itself, but may also be on an associated regulatory protein.
Potassium channel openers represent a widely diverse series of compounds which all have the reported effect of opening only a subset of channels described as sensitive to ATP. As explained above, these compounds cause physiological responses by increasing membrane permeability to potassium, this leads to hyperpolarization of the cell membrane and temporal desensitization to electrical and chemical stimuli.
Openers which target these channels have been synthesized as possible drugs in hypertension, angina pectoris, coronary heart disease, asthma, and urinary incontinence. There are various references which describe potassium channel openers:
Cook et al., xe2x80x9cPotassium Channels: Structure, Classification, Function and TherapeuticPotentialxe2x80x9d, ed. N. S. Cook, Ellis Horwood, Chichester (1990), p.p. 181-255;
David W. Robertson et al. , Journal of Medicinal Chemistry, xe2x80x9cPotassium Channel Modulators: Scientific Applications and Therapeutic Promise,xe2x80x9d vol. 33, No. 6, June 1990, pp. 1529-1541;
Gillian Edwards et al., xe2x80x9cStructure-Activity Relationships of K+Channel Openers,xe2x80x9d vol. 11, No. 10, October 1990, pp. 417-422;
Valerie A. Ashwood et al., xe2x80x9cSynthesis and Antihypertensive Activity of Pyran Oxygen and Amide Nitrogen Replacement Anal oges of the Potassium Channel Activator Cromakalim,xe2x80x9d Journal of Medicinal Chemistry, vol. 34, No. 11, November 1991, pp. 3261-3267;
Susan D. Longman et al., xe2x80x9cPotassium Channel Activator Drugs: Mechanism of Action, Pharmacological Properties, and Therapeutic Potential,xe2x80x9d Medicinal Research Reviews, vol. 12, No. 2, Mar. 1, 1992, pp. 73-148; and
Karnail S. Atwal, xe2x80x9cModulation of Potassium Channels by Organic Molecules,xe2x80x9d Medicinal Research Reviews, vol. 12, No. 6, November 1992, pp. 569-591.
Agents which elevate cGMP levels are also well known and can work through any of several mechanisms. Agents which selectively inhibit an enzyme predominantly involved in cGMP breakdown, for example a cGMP phosphodiesterase (cGMP PDE), constitute one example. Other phosphodiesterases can also hydrolyze cGMP, and inhibitors of these enzymes including compounds such as rolipram, zaprinast and xanthine derivatives such as caffeine, theophylline and theobromine, can accordingly influence cGMP levels. Other compounds which increase cGMP levels can do so through different mechanisms including the activation of soluble guanylate cyclase or membrane-bound guanylate cyclase, either directly as in the case of atrial natriuretic peptide, or indirectly. Other compounds act to increase cellular cGMP levels by modulation of cytokines. Other classes of cGMP elevators include muscarinic agonists, which can elevate cGMP levels without altering phosphodiesterase activity. Some prostaglandins such as PGE1 are also known cGMP elevators. Kanba et. al., J. Neurochem., Vol. 57, No. 6,1991.
Cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterase (cGMP PDE) inhibitors are widely known as cardiovascular agents for the treatment of conditions such as angina, hypertension, and congestive heart failure. More recently cGMP PDE inhibitors have been found to be effective for the treatment of impotence, importantly by oral administration. See, for example, PCT/EP94/01580, published as WO 94/28902. It is believed that such compounds may manifest their therapeutic effects by achieving high cGMP levels through inhibiting phosphodiesterase, thereby relaxing and expanding cavernosal cells and blocking the outflow of blood from the penis.
This invention provides a method of treating impotence (also known in the art and referred to herein as xe2x80x9cmale erectile dysfunctionxe2x80x9d), especially in humans, comprising co-administering to a patient in need of such treatment an effective amount of:
(1) a compound selected from potassium channel openers (also referred to as potassium channel activators), and
(2) a compound which elevates cGMP levels (herein also referred to as a cGMP elevator).
Reference to a compound or agent within the scope of (1) or (2), above, such as to a potassium channel opener and/or to a cGMP elevator, both in this disclosure and the appendant claims, shall at all times be understood to include all active forms of such agents, including the free form thereof (e.g., the free acid or base form) and also all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates, solvates, isomers, stereoisomers (e.g. diastereomers and enantiomers), tautomers, and so forth. Active metabolites of either the potassium channel openers or the cGMP elevator, in any form, are also included.
As the cGMP elevator, cGMP PDE inhibitors are preferred. cGMP PDE inhibitors which are selective for cGMP PDEs rather than cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cAMP PDEs) and/or which are selective inhibitors of the cGMP PDEv isoenzyme are particularly preferred. Such particularly preferred cGMP PDE inhibitors are disclosed in U.S. Pat. Nos. 5,250,534, 5,346,901, 5,272,147, and in the international patent application published as WO 94/28902 designating, inter alia, the U.S., each of which is incorporated herein by reference.
Preferred combinations of a potassium channel opener and a cGMP PDE elevator useful herein are xe2x80x9csynergisticxe2x80x9d, meaning that the therapeutic effect of co-administering compounds selected from (1) and (2) as defined above is greater than additive. Thus, co-administering both therapeutic agents produces an effect which is greater than the sum of the effects of each agent administered alone. Such synergy is advantageous in that it allows for each therapeutic agent typically to be administered in an amount less than if the combined therapeutic effects were additive. Thus, therapy can be effected for patients who, for example, do not respond adequately to the use of one component at what would be considered a maximal strength dose. Additionally, by administering the components in lower amounts relative to the case where the combined effects are additive, side effects such as any priapism or pain at the site of injection can be minimized or avoided in many cases. Such synergy can be demonstrated by the tests disclosed below.
The synergy of such preferred combinations is provided as a further feature of the invention, and accordingly the invention provides a method for achieving a synergistic therapeutically effective level of impotence treatment, comprising co-administering to a mammal in need of such treatment
(1) an amount of a first compound selected from potassium channel openers; and
(2) an amount of a second compound selected from compounds which elevate cGMP levels;
wherein the amount of the first compound alone and the amount of the second compound alone are each insufficient to achieve the synergistic therapeutically effective level of impotence treatment, but wherein the combined effect of the amounts of the first and second compounds is greater than the sum of the levels of therapeutic effects of impotence treatment achievable with the individual amounts of the first and second compound.
Additional preferred combinations include those which can be taken xe2x80x9con demandxe2x80x9d, as opposed to needing to be taken chronically. Such preferred combinations include those which modulate the sexual response such that the patient responds to sexual (e.g., visual) stimulation, as opposed to compositions which act by causing an erection in the absence of sexual stimulation.
Additional preferred combinations include those which are xe2x80x9cfast actingxe2x80x9d, meaning that the time from administration to the point at which the sexual response can be modulated is less than about two hours, preferably less than about one hour, more preferably on the order of a half hour or less, and even more preferably within 10 to 15 minutes.
xe2x80x9cCo-administrationxe2x80x9d when used in this disclosure and the appendant claims, for example in referring to a combination of a potassium channel openers and a cGMP PDE inhibitor, means that the individual components can be administered together as a composition if the route of administration for each component is the same. Thus the invention further provides a composition comprising
(1) a first compound, said first compound being selected from potassium channel openers;
(2) a second compound which elevates cGMP levels; and
(3) a pharmaceutically acceptable vehicle, diluent or carrier. A preferred group of compositions are synergistic. Such synergistic compositions, which are provided as a further feature of the invention, comprise
(1) an amount of a first compound selected from potassium channel openers;
(2) an amount of a second compound selected from compounds which elevate cGMP levels;
wherein the amount of the first compound alone and the amount of the second compound alone are each insufficient to achieve a synergistic therapeutically effective level of impotence treatment, but wherein the effect of a composition comprising said amounts of said first and second compounds is greater than the sum of the levels of therapeutic effects of impotence treatment achievable with the individual amounts of said first and second compound; and a pharmaceutically acceptable vehicle, diluent or carrier.
xe2x80x9cCo-administrationxe2x80x9d also includes administering each of compounds (1) and (2) separately but as part of the same therapeutic treatment program or regimen, and it is contemplated that separate administration of each compound, at different times and by different routes, will sometimes be recommended. Thus, the two compounds need not necessarily be administered at essentially the same time or in any order. In a preferred embodiment, administration is timed so that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect for the other. If co-administered separately, it is also preferred that both of compounds (1) and (2) be administered in an oral dosage form.
Reference herein to a xe2x80x9ccombinationxe2x80x9d is to the co-administration of a compound selected from (1) and a compound selected from (2), each as defined above, either as a composition or separately, e.g., by different routes of administration.
The compositions of this invention are also useful for the treatment of sexual dysfunction in female mammals, including humans. Thus the compositions are useful, for example, in the treatment of female sexual dysfunction including orgasmic dysfunction related to clitoral disturbances. As in the case of male mammals, compositions which are synergistic, which can be taken on demand, and which modulate the female sexual response are preferred. Preferred compounds, compositions, and combinations (e.g. of compounds for separate administration) for the treatment of female sexual dysfunction are the same as those disclosed herein for the treatment of male erectile dysfunction.
Methods for the treatment of female sexual dysfunction are analogous to those presented herein for the treatment of impotence or erectile dysfunction in male animals.
Since the present invention has an aspect that relates to the treatment of impotence or of female sexual dysfunction by treatment with a combination of compounds which may be co-administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: (1) a composition comprising a compound selected from potassium channel openers, and a pharmaceutically acceptable vehicle, diluent or carrier; and (2) a composition comprising a compound selected from agents which elevate cGMP levels, and a pharmaceutically acceptable vehicle, diluent or carrier and a container. The amounts of (1) and (2) are such that, when co-administered separately, the impotence condition or condition of female sexual dysfunction is treated and/or remediated. The kit comprises a means for containing the separate compositions such as a container, divided bottle or a divided foil packet, wherein each compartment contains a plurality of dosage forms (e.g., tablets) comprising (1) or (2). Alternatively, rather than separating the active ingredient-containing dosage forms, the kit may contain separate compartments each of which contains a whole dosage which in turn comprises separate dosage forms. An example of this type of kit is a blister pack wherein each individual blister contains two (or more) tablets, one (or more) tablet(s) comprising pharmaceutical composition (1), and the second one (or more) tablet(s) comprising pharmaceutical composition (2). Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. In the case of the instant invention a kit therefore comprises a therapeutically effective amount of
(1) a composition comprising a compound selected from potassium channel openers, and a pharmaceutically acceptable vehicle, diluent or carrier, in a first dosage form;
(2) a composition comprising a compound selected from compounds which elevate cGMP levels, and a pharmaceutically acceptable vehicle, diluent or carrier, in a second dosage form; and
(3) a container for containing said first and second dosage forms.
An example of such a kit, alluded to above, is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms such as tablets, capsules, and the like. Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. Tablet(s) or capsule(s) can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen during which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . . xe2x80x9d, etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of the first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
Other pharmaceutical components may also be optionally included as part of the combinations useful in this invention so long as they do not interfere or adversely affect the effects of the potassium channel opener/cGMP elevator combination.
Preferred combinations further include (1) a cGMP PDE inhibitor and any suitably potent potassium channel opener such as nicorandil; and (2) a cGMP PDE inhibitor that is selective for the PDEV isoenzyme. Compounds selective for the PDEv isoenzyme are disclosed, for example, in PCT/EP94/01580, published as WO 94/28902 and which designates, inter alia, the United States, and which is incorporated herein by reference.
Preferred cGMP PDE inhibitors include sildenafil which has the structure: 
and pharmaceutically acceptable salts thereof, and the compound having the structure: 
and pharmaceutically acceptable salts thereof. The second compound is disclosed, for example, in U.S. Pat. Nos. 5,272,147 and 5,426,107, both incorporated herein by reference.
Other preferred cGMP PDE inhibitors include 3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2)2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethyl-4-oxidopiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-(2-methoxyethyoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7-Hpyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-(6-methylpyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(6-methoxypyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-i-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,3-diethyl-2,6-dihydro-7H -pyrazolo[[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[1-pyridin-2-yl)ethyl]2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one or the pharmaceutically acceptable salts thereof
A preferred pharmaceutically acceptable salt of sildenafil for use in this invention is the citrate salt.
Also preferred are compounds disclosed in PCT/EP95/00183, published as WO 95/19978 designating, inter alia, the United States, and herein incorporated by reference, said compounds having the formula 
and salts and solvates thereof, in which:
R0 represents hydrogen, halogen or C1-6alkyl,;
R1 represents hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, C3-8cycloalkyl, C3-8cycloalkylC1-3alkyl, arylC1-3alkyl or heteroarylC1-3alkyl;
R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring 
xe2x80x83attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and
R3 represents hydrogen or C1-3alkyl, or R1 and R3 together represent a 3- or 4-membered alkyl or alkenyl chain.
A preferred subset of compounds having formula Ia (also disclosed in WO 95/19978) includes compounds of the formula 
and salts and solvates thereof, in which:
R0 represents hydrogen, halogen or C1-6alkyl;
R1 represents hydrogen, C1-6alkyl, haloC1-6alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-3alkyl, arylC1-3alkyl or heteroarylC1-3alkyl; and
R2 represents an optionally substituted monocyclic aromatic ring selected from benzene thiophene, furan and pyridine or an optionally substituted bicyclic ring 
xe2x80x83attached to the rest of the molecule via one of the benene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen.
A specific compound within formula (I) is:
(6R, 12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2xe2x80x2,1xe2x80x26,1]pyrido[3,4-b]indole-1,4-dione.
Preferred potassium channel openers include nicorandil, diazoxide, cromakalim, levcromakalim, pinacidil, lemakalim and minoxidil and also pharmaceutically acceptable salts or isomers thereof. Especially preferred potassium channel openers include nicorandil, diazoxide and minoxidil. Preferred specific combinations include any of these in combination with sildenafil or a pharmaceutically acceptable salt thereof, particularly the citrate salt. Most preferred are sildenafil citrate in combination with nicorandil. A variety of potassium channel openers are described in U.S. Pat. Nos. 5,464,867; 5,466,712; 5,403,853; 5,403,854; 5,397,790; 5,401,753; 5,872,139; and 5,905,156, the teachings of which are incorporated herein by reference.
Specific combinations of a potassium channel opener and a cGMP elevator useful in this invention include any potassium channel opener in combination with sildenafil. Combinations of sildenafil, especially sildenafil citrate, with a potassium channel opener, including any of those previously noted, are preferred.